Gene Therapy for Leber Hereditary Optic Neuropathy
Open accessAbstract
Purpose Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome.Design In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 × 10(9) vg), and the fourth participant was treated at the medium dose (2.46 × 10(10) vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations.Participants Five legally blind patients with G11778A LHON.Main outcome measures Loss of visual acuity.Results Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA.Conclusions No serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations.
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In that trial, data and BCVA curves showed bilateral improvement in BCVA in 7 patients (50%), with follow-up from 3 to 18 months.
“The data and BCVA curves provided showed a bilateral improvement in BCVA in 7 patients (50%), with a follow-up from 3 to 18 months.35,36”
From Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset (2021) · cites this paper as [35]
The Abstract (Design) describes five participants followed for 90–180 days, not seven patients with follow-up extending to 18 months. The Results (Visual Function) report no acuity change in three participants and improvement in two; they do not report bilateral improvement in seven patients (50%). (LLM, conf=0.90)
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Experimental — accuracy not yet measuredDifferent trials have demonstrated the safety and efficacy of gene therapy using an AAV vector, delivered through an intravitreal route, for LHON.
“Different trials have demonstrated the safety and efficacy of gene therapy using an AAV vector, delivered through an intravitreal route, for LHON.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [63]
The Design and Results sections describe one intravitreal AAV trial in five people with LHON: no serious adverse events were observed, and two participants had improved visual acuity. The Conclusions call these observations preliminary and say further follow-up is needed. This paper therefore supports early safety findings and possible benefit, but not the claim that different trials have demonstrated safety and efficacy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGuy et al conducted a prospective, dose-escalation, open-label trial including 14 LHON subjects aged 18 years or older who were unilaterally injected with self-complementary adeno-associated vector 2-ND4.
“They conducted a prospective, dose-escalation, open-label trial, including 14 LHON subjects who were 18 years or older and unilaterally injected with self-complementary adeno-associated vector 2-ND4.”
From Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset (2021) · cites this paper as [35]
The Abstract (Design) and Methods describe a prospective, open-label, dose-escalation LHON trial using unilateral injections of a self-complementary AAV2-ND4 vector. But the Abstract (Design) and Results (Study Entry and Dosing) report five injected participants, not 14. The retrieved passages do not establish the stated minimum age of 18. (LLM, conf=0.91)
Experimental — accuracy not yet measuredSimilar improvement in visual function of the untreated eye after unilateral intravitreal administration of a viral vector containing cDNA encoding human wild-type mitochondrial ND4 protein was observed in clinical studies from 2 other gene therapy programs for m.11778G>A LHON, one in China and one in the United States.
“Indeed, similar improvement in visual function of the untreated eye after unilateral intravitreal administration of a viral vector containing a cDNA encoding the human wild-type mitochondrial ND4 protein was observed in clinical studies from 2 other gene therapy programs for LHON caused by the m.11778G>A mutation, 1 in China and 1 in the United States.”
From Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset (2021) · cites this paper as [35]
Guy et al developed a self-complementary adeno-associated vector with a nuclear-encoded ND4 and an appended MTS for allotopic rescue of the m.11778G>A mutation.
“Guy et al, 35,36 at the University of Miami, have also developed a self-complementary adeno-associated vector with a nuclear-encoded ND4 and an appended MTS for allotopic rescue of the m.11778G> mutation.”
From Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset (2021) · cites this paper as [35]
Two similar gene therapy programmes led by groups in the USA and China targeted the m.11778G>A mutation in MT-ND4 using a viral vector containing a cDNA coding the human wild-type mitochondrial ND4 protein.
“Two similar gene therapy programmes led by groups in the USA25,26 and China,27–30 have targeted the m.11778G>A mutation in MT-ND4, also using a viral vector containing a cDNA coding the human wild-type mitochondrial ND4 protein.”
From Randomized trial of bilateral gene therapy injection for m.11778G&gt;A <i>MT-ND4</i> Leber optic neuropathy (2023) · cites this paper as [25]
Two clinical trials employing IVI of AAV2-based vectors to address LHON caused by mutations in mitochondrial ND4 documented high antibody titers and anterior uveitis in some treated patients.
“Two clinical trials employing IVI of AAV2-based vectors to address LHON caused by mutations in mitochondrial ND4 (ClinicalTrials.gov: NCT02161380 and NCT02064569) documented high antibody titers and anterior uveitis in some treated patients.125,126,132,133”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [126]
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References 47 · Cited by 230
- Authors
- Feuer, W. J., Schiffman, J. C., Davis, J. L., Porciatti, V., Gonzalez, P., Koilkonda, R. D., Yuan, H., Lalwani, A., Lam, B. L., & Guy, J.
- Affiliations
- University of Miami (US)
- Corresponding author
- Guy, John
- ORCID
- Venue
- Ophthalmology
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 123
- Issue
- 3
- Pages
- 558-570
- ISSN
- 0161-6420 (ISSN-L)
- PMC
- PMC5287094
- OpenAlex
- W2260846512
- Cited by
- 230
- References
- 47
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 10 · 2023: 16 · 2022: 23 · 2021: 27 · 2020: 22 · 2019: 28 · 2018: 26 · 2017: 31 · 2016: 25
- FWCI
- 18.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Ophthalmology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health and Human Services (1U10EY024247-01, P30EY014801, 1U10EY023558-01A1, W81XWH-09-1-0675)
- National Institutes of Health (1U10EY024247-01, P30EY014801, 1U10EY023558-01A1, W81XWH-09-1-0675)
- National Eye Institute (1U10EY024247-01, P30EY014801, 1U10EY023558-01A1, W81XWH-09-1-0675)
- Research to Prevent Blindness (1U10EY024247-01, P30EY014801, 1U10EY023558-01A1, W81XWH-09-1-0675)
- U.S. Department of Defense (1U10EY024247-01, P30EY014801, 1U10EY023558-01A1, W81XWH-09-1-0675)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Keywords
- Leber's hereditary optic neuropathy, gene therapy, adeno-associated virus vectors, AAV2, ND4, mitochondrial DNA mutations, intravitreal injection, visual acuity, safety and tolerability, neutralizing antibodies, mitochondrial disease, vision loss, intraocular pressure, exposure keratopathy
- MeSH terms
- Dependovirus, Adult, DNA, Mitochondrial, Electroretinography, Female, Genetic Vectors, Humans, Male, Middle Aged, NADH Dehydrogenase, Prospective Studies, Visual Acuity, Visual Fields, Genetic Therapy, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Optic Atrophy, Hereditary, Leber, Tomography, Optical Coherence, Intravitreal Injections, Visual Field Tests
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